Cancer is an age-related disease. In humans and mice, cancer incidence increases exponentially with age. However, the mechanisms for how aging affects cancer development remain poorly understood. The primary goal of the proposed research is to explore potential mechanisms by which aging increases cancer susceptibility. We will examine components of oncogenic signaling in the context of aging likely to be important in cancer development. First, we will analyze the effects of tumor suppressor p53 loss at different ages in the mouse to show that p53 loss in aged tissues is more deleterious than in young tissues. Second, we will compare the effects of oncogene activation at various ages in the lungs of mice. We hypothesize that cells become more susceptible to oncogenic transformation in the aged tissue environment and that the cellular defense systems to counteract transformation events become less effective in that same aged environment. In this proposal, we will use genetically engineered mouse models to activate the mutant K-Ras oncogene or inactivate the p53 tumor suppressor gene at different ages to determine whether age-associated differences in cancer signaling and stress response pathways exist and whether these differences affect the biology of cancer development and progression. Two aims are proposed. In the first aim, we will globally delete the p53 tumor suppressor gene at different ages and compare the kinetics,biology, and gene expression patterns characteristic of tumors losing p53 function at young and old ages. We will also perform experiments to explore a novel model of p53 anti-cancer function: that p53 not only acts as a late gatekeeper to prevent malignant progession, but also as an early caretaker to suppress genomic instability during early development. In the second aim, we will activate a mutant K-Ras oncogene in the lung at 3, 12, and 24 months of age. We will monitor the progression of tumorigenesis in these K- Ras-activated mice and also examine whether oncogenic signaling pathways and cellular anti-oncogenic stress pathways are affected by age. From these experiments we hope to gain important new mechanistic insights into how aging tissues affect cancer susceptibility. PUBLIC HEALTH RELEVANCE: Cancer incidence rates are greatly elevated in the final third of the human lifespan. The median age for cancer diagnosis in industrialized countries is near 70 and will increase in the coming years, placing enormous burdens on health care systems. Having a better understanding of how and why aging tissues become cancer susceptible may provide oncologists with better tools for fighting cancer in the elderly.